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Low-Grade Serous Ovarian Cancer

Panelists: Michael J. Birrer, MD, PhD, The University of Alabama at Birmingham; Robert L. Coleman, MD, FACOG, FACS, The University of Texas MD Anderson Cancer Center; Bradley J. Monk, MD, FACS, FACOG, The University of Arizona College of Medicine; Kathleen Moore, MD, The University of Oklahoma Health and Sciences Center; Shannon N. Westin, MD, MPH, The University of Texas MD Anderson Cancer Center
Published: Monday, Dec 02, 2019



Transcript:

Bradley J. Monk, MD, FACS, FACOG: We have spent a lot of time talking about high-grade serous and even high-grade endometrioid tumors, but we realize it’s heterogeneous. Fallopian tube and peritoneal cancers are certainly included. Rob, I want you to tell us about this subset called low-grade serous ovarian cancer and how that differs both molecularly and clinically.

Robert L. Coleman, MD, FACOG, FACS: Low-grade serous cancer occurs in about 5% to 10% of the new ovarian cancer patients. It looks to be a disease that is reflective of the non-P53-generated type pathways—mostly MAP kinase and the PI3 kinase pathway. There are some patients who have P53 mutations, but they’re frequently mixed, high- and low-grade serous. It’s clearly a different disease. It has a different biology and a different natural history.

Bradley J. Monk, MD, FACS, FACOG: Slower growing.

Robert L. Coleman, MD, FACOG, FACS: Yes. Interestingly, in the studies where we’ve looked at this, at least retrospectively, the progression-free survival [PFS] is not too dissimilar from high-grade serous. However, the overall survival is much longer.

Bradley J. Monk, MD, FACS, FACOG: There you go.

Robert L. Coleman, MD, FACOG, FACS: There is something about its molecular characteristics that have driven this particular biology. We were very excited to start to dig into this and separate it from high-grade serous so we could start to focus on it as its own entity. The trial that was reported here by…

Bradley J. Monk, MD, FACS, FACOG: Before we get to that, I want to talk about the differences. Is ovarian cancer hard to image, Michael? Is it hard to image? Is it like a lung tumor, where we can put some calipers on it?

Michael J. Birrer, MD, PhD: Are you trying to set me up?

Bradley J. Monk, MD, FACS, FACOG: I am trying to. I’m trying to get you to teach the audience that it comes to biosimilars. The regulators say, “You better study lung cancer because it’s easy to measure.”

Robert L. Coleman, MD, FACOG, FACS: This is hard.

Bradley J. Monk, MD, FACS, FACOG: They don’t say, “Oh, let’s do it in ovarian cancer because those CT [computed tomography] scans are easy to read.”

Robert L. Coleman, MD, FACOG, FACS: It’s hard.

Bradley J. Monk, MD, FACS, FACOG: That’s why we use placebos and blinded independent central reviews.

Michael J. Birrer, MD, PhD: You’re absolutely right. Carcinomatosis is not easy. The ascites can’t be quantified.

Robert L. Coleman, MD, FACOG, FACS: It’s particularly difficult with low-grade because we oftentimes see cystic and calcific lesions as the metastatic disease. Sometimes under therapy, when we see responses, we still see calcific cystic masses, so you don’t even know if it’s going away. How do you measure a lesion that has a solid cystic and a calcific component?

Bradley J. Monk, MD, FACS, FACOG: Yes. Tell us about the molecular biology of these tumors. We know the molecular biology of high-grade serous, P53, BRCA, and genomic instability. What about low-grade serous?

Michael J. Birrer, MD, PhD: I think it evolved over the last 5 to 10 years. It’s clearly a separate disease. If you compare it with high-grade, that obviously has ubiquitous P53 mutations and abnormalities in HRD [homologous recombination deficiency]. We’ve already talked about that. You don’t see any of that in low grades. In fact, P53 is sometimes used as a biomarker to distinguish the 2. Instead, what you see is KRAS mutations. You see multiple mutations that activate the MAP kinase pathway. That looks like a driver, and that’s the genesis of this whole effort.

Bradley J. Monk, MD, FACS, FACOG: We have therapeutic targets in the RAS/RAF/MEK/ERK inhibitors. I want to mention that Rachel Grisham of Memorial Sloan Kettering Cancer Center presented a study at the International Gynecologic Cancer Society 2019 Global Meeting of a MEK inhibitor called binimetinib versus physician’s choice chemotherapy. It was exactly like FORWARD 1, a drug that worked and had a response rate of almost 25% but was not better than an active comparator. The end point was blinded independent central review because, again, there’s no placebo. One patient is getting the pill, and the other patient is getting IV [intravenous] chemotherapy. There was a second low-grade serous MEK inhibitor trial presented at ESMO [the European Society for Medical Oncology Congress] 2019, called GOG-0281. Either of you can tell me about it.

Shannon N. Westin, MD, MPH: GOG-0281, a really nicely designed trial, randomized patients with low-grade serous. It was not molecularly selected. Any patient could go on and was randomized to either trametinib, which is a MEK inhibitor, or physician’s choice treatment—not just chemotherapy. There were 5 different options that patients could be treated with: letrozole, tamoxifen, weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin.

Bradley J. Monk, MD, FACS, FACOG: In the binimetinib MILO trial, there was no hormone option.

Shannon N. Westin, MD, MPH: No hormone option. That’s right. Yes.

Bradley J. Monk, MD, FACS, FACOG: Keep going.

Shannon N. Westin, MD, MPH: Our sense was that the hormones are better for these patients. We were more excited about this trial in some ways because we had that option. They were randomized 1:1. The primary end point was progression-free survival, and it also looked at things like toxicity, quality of life, response rate, and overall survival. Spoiler alert: it was positive.

Robert L. Coleman, MD, FACOG, FACS: Yes, and what’s also unique in the MILO trial was that crossover was allowed.

Shannon N. Westin, MD, MPH: That’s a great point, yes.

Bradley J. Monk, MD, FACS, FACOG: But the end point is progression-free survival.

Shannon N. Westin, MD, MPH: Yes, progression-free survival, but the patients were allowed to cross over.

Bradley J. Monk, MD, FACS, FACOG: Were hormones better than chemotherapy, as you said?

Shannon N. Westin, MD, MPH: They were.

Bradley J. Monk, MD, FACS, FACOG: How much better?

Shannon N. Westin, MD, MPH: I think response rates to letrozole were somewhere around 13%.

Bradley J. Monk, MD, FACS, FACOG: Thirteen percent.

Robert L. Coleman, MD, FACOG, FACS: Thirteen percent, yes.

Shannon N. Westin, MD, MPH: Thirteen percent, and the tamoxifen not as much. I think it was a 0.0% response rate.

Michael J. Birrer, MD, PhD: I’d love to hear your opinion on it, Brad. Was that the response rate to pegylated liposomal doxorubicin? Two percent?

Bradley J. Monk, MD, FACS, FACOG: That’s right.

Michael J. Birrer, MD, PhD: What was it in your study?

Bradley J. Monk, MD, FACS, FACOG: Over 20%. How is that possible that a biased observer in an open-label trial, in a disease that’s hard to measure, could have a different result in a blinded independent central review? How is that possible? You can say, “I get it. Letrozole had some activity—half of what chemotherapy had in MILO. It had some. I think it’s a self-fulfilling prophecy. I don’t mean to say 1 trial was better than the other. I say it takes 2 trials to convince anyone of anything, and these trials are in contradiction.

Michael J. Birrer, MD, PhD: I could give you an alternative hypothesis. Maybe you had high-grades in your study.

Bradley J. Monk, MD, FACS, FACOG: In our study, to your point, we had independent pathology review by your pathologist.

Robert L. Coleman, MD, FACOG, FACS: Correct.

Michael J. Birrer, MD, PhD: There’s the problem.

Robert L. Coleman, MD, FACOG, FACS: You’re right, and we had central review for GOG-0281, as well.

Bradley J. Monk, MD, FACS, FACOG: That’s right. I think the take-home message is that clinical trial design matters, but I think that this is an active class of agents.

Shannon N. Westin, MD, MPH: Absolutely.

Bradley J. Monk, MD, FACS, FACOG: If you look at the progression-free survival of MILO and GOG-0281, the curves overlap.

Shannon N. Westin, MD, MPH: They’re right on top of each other, yes.

Bradley J. Monk, MD, FACS, FACOG: The only thing that’s different is the control arm.

Shannon N. Westin, MD, MPH: Yes.

Bradley J. Monk, MD, FACS, FACOG: And the way that the control arm was assessed. I’m not sure that 1 is positive or negative. I would hope that the NCCN [National Comprehensive Cancer Network] and others would recognize this class of agents as an opportunity.

Robert L. Coleman, MD, FACOG, FACS: I do too. This is a disease in which, because of a long postprogression survivorship, we end up going through all these agents.

Kathleen Moore, MD: Twice.

Bradley J. Monk, MD, FACS, FACOG: Twice, Katie Moore says.

Kathleen Moore, MD: Yes.

Robert L. Coleman, MD, FACOG, FACS: We need these options. The other thing that was interesting—that’s why I mentioned the crossover—was that when we looked at the efficacy in the crossover, we still saw…

Kathleen Moore, MD: It was less, though.

Robert L. Coleman, MD, FACOG, FACS: It was less, but it was 15%. The PFS was close to 10 months.

Shannon N. Westin, MD, MPH: Yes, 10 months.

Robert L. Coleman, MD, FACOG, FACS: We need this drug.

Bradley J. Monk, MD, FACS, FACOG: We do need this class of drug.

Robert L. Coleman, MD, FACOG, FACS: Class of drug. Yes, we need this class of drug.

Kathleen Moore, MD: You’re right. The studies were contradictory because of the control arm, but I also think they were consistent in that they showed efficacy. I agree with you. I feel like the NCCN should—I’m just going to say it—put it on compendium so we don’t have to fight for our patients.

Michael J. Birrer, MD, PhD: The other thing is that I think it’s already being used. We’ve been using it off-label for a long time.

Bradley J. Monk, MD, FACS, FACOG: It’s difficult to get reimbursed with that.

Robert L. Coleman, MD, FACOG, FACS: Getting back to the molecular biology in the tumor, both of these studies have pretty robust TR components coming. We’re going to dig into that.

Bradley J. Monk, MD, FACS, FACOG: In MILO, we reported that, and there was a KRAS-predictive biomarker.

Robert L. Coleman, MD, FACOG, FACS: The idea is that we’ve learned that it’s not necessarily just KRAS. It’s KRAS-specific mutation.

Bradley J. Monk, MD, FACS, FACOG: That’s true.

Robert L. Coleman, MD, FACOG, FACS: So we see different…with the KRAS G12D—the common ones—we don’t see as great of a discriminator, but we do see the G12Ds. I mean, Vs and Cs. In the Vs and Cs, we see a difference.

Michael J. Birrer, MD, PhD: In GOG-239 it was phospho-ERK. It was downstream. It was a very good marker.

Bradley J. Monk, MD, FACS, FACOG: We’re better at biomarkers now, I think.

Robert L. Coleman, MD, FACOG, FACS: It’s great.

Bradley J. Monk, MD, FACS, FACOG: It’s fun, huh? It’s fun. It’s fun to realize that ovarian cancer is heterogeneous. It’s fun to understand biomarkers, and it’s fun to give our patients—when I say fun, I mean satisfying. Fun is not the right word. It’s satisfying to help our patients with targeted therapy.

Transcript Edited for Clarity

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Transcript:

Bradley J. Monk, MD, FACS, FACOG: We have spent a lot of time talking about high-grade serous and even high-grade endometrioid tumors, but we realize it’s heterogeneous. Fallopian tube and peritoneal cancers are certainly included. Rob, I want you to tell us about this subset called low-grade serous ovarian cancer and how that differs both molecularly and clinically.

Robert L. Coleman, MD, FACOG, FACS: Low-grade serous cancer occurs in about 5% to 10% of the new ovarian cancer patients. It looks to be a disease that is reflective of the non-P53-generated type pathways—mostly MAP kinase and the PI3 kinase pathway. There are some patients who have P53 mutations, but they’re frequently mixed, high- and low-grade serous. It’s clearly a different disease. It has a different biology and a different natural history.

Bradley J. Monk, MD, FACS, FACOG: Slower growing.

Robert L. Coleman, MD, FACOG, FACS: Yes. Interestingly, in the studies where we’ve looked at this, at least retrospectively, the progression-free survival [PFS] is not too dissimilar from high-grade serous. However, the overall survival is much longer.

Bradley J. Monk, MD, FACS, FACOG: There you go.

Robert L. Coleman, MD, FACOG, FACS: There is something about its molecular characteristics that have driven this particular biology. We were very excited to start to dig into this and separate it from high-grade serous so we could start to focus on it as its own entity. The trial that was reported here by…

Bradley J. Monk, MD, FACS, FACOG: Before we get to that, I want to talk about the differences. Is ovarian cancer hard to image, Michael? Is it hard to image? Is it like a lung tumor, where we can put some calipers on it?

Michael J. Birrer, MD, PhD: Are you trying to set me up?

Bradley J. Monk, MD, FACS, FACOG: I am trying to. I’m trying to get you to teach the audience that it comes to biosimilars. The regulators say, “You better study lung cancer because it’s easy to measure.”

Robert L. Coleman, MD, FACOG, FACS: This is hard.

Bradley J. Monk, MD, FACS, FACOG: They don’t say, “Oh, let’s do it in ovarian cancer because those CT [computed tomography] scans are easy to read.”

Robert L. Coleman, MD, FACOG, FACS: It’s hard.

Bradley J. Monk, MD, FACS, FACOG: That’s why we use placebos and blinded independent central reviews.

Michael J. Birrer, MD, PhD: You’re absolutely right. Carcinomatosis is not easy. The ascites can’t be quantified.

Robert L. Coleman, MD, FACOG, FACS: It’s particularly difficult with low-grade because we oftentimes see cystic and calcific lesions as the metastatic disease. Sometimes under therapy, when we see responses, we still see calcific cystic masses, so you don’t even know if it’s going away. How do you measure a lesion that has a solid cystic and a calcific component?

Bradley J. Monk, MD, FACS, FACOG: Yes. Tell us about the molecular biology of these tumors. We know the molecular biology of high-grade serous, P53, BRCA, and genomic instability. What about low-grade serous?

Michael J. Birrer, MD, PhD: I think it evolved over the last 5 to 10 years. It’s clearly a separate disease. If you compare it with high-grade, that obviously has ubiquitous P53 mutations and abnormalities in HRD [homologous recombination deficiency]. We’ve already talked about that. You don’t see any of that in low grades. In fact, P53 is sometimes used as a biomarker to distinguish the 2. Instead, what you see is KRAS mutations. You see multiple mutations that activate the MAP kinase pathway. That looks like a driver, and that’s the genesis of this whole effort.

Bradley J. Monk, MD, FACS, FACOG: We have therapeutic targets in the RAS/RAF/MEK/ERK inhibitors. I want to mention that Rachel Grisham of Memorial Sloan Kettering Cancer Center presented a study at the International Gynecologic Cancer Society 2019 Global Meeting of a MEK inhibitor called binimetinib versus physician’s choice chemotherapy. It was exactly like FORWARD 1, a drug that worked and had a response rate of almost 25% but was not better than an active comparator. The end point was blinded independent central review because, again, there’s no placebo. One patient is getting the pill, and the other patient is getting IV [intravenous] chemotherapy. There was a second low-grade serous MEK inhibitor trial presented at ESMO [the European Society for Medical Oncology Congress] 2019, called GOG-0281. Either of you can tell me about it.

Shannon N. Westin, MD, MPH: GOG-0281, a really nicely designed trial, randomized patients with low-grade serous. It was not molecularly selected. Any patient could go on and was randomized to either trametinib, which is a MEK inhibitor, or physician’s choice treatment—not just chemotherapy. There were 5 different options that patients could be treated with: letrozole, tamoxifen, weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin.

Bradley J. Monk, MD, FACS, FACOG: In the binimetinib MILO trial, there was no hormone option.

Shannon N. Westin, MD, MPH: No hormone option. That’s right. Yes.

Bradley J. Monk, MD, FACS, FACOG: Keep going.

Shannon N. Westin, MD, MPH: Our sense was that the hormones are better for these patients. We were more excited about this trial in some ways because we had that option. They were randomized 1:1. The primary end point was progression-free survival, and it also looked at things like toxicity, quality of life, response rate, and overall survival. Spoiler alert: it was positive.

Robert L. Coleman, MD, FACOG, FACS: Yes, and what’s also unique in the MILO trial was that crossover was allowed.

Shannon N. Westin, MD, MPH: That’s a great point, yes.

Bradley J. Monk, MD, FACS, FACOG: But the end point is progression-free survival.

Shannon N. Westin, MD, MPH: Yes, progression-free survival, but the patients were allowed to cross over.

Bradley J. Monk, MD, FACS, FACOG: Were hormones better than chemotherapy, as you said?

Shannon N. Westin, MD, MPH: They were.

Bradley J. Monk, MD, FACS, FACOG: How much better?

Shannon N. Westin, MD, MPH: I think response rates to letrozole were somewhere around 13%.

Bradley J. Monk, MD, FACS, FACOG: Thirteen percent.

Robert L. Coleman, MD, FACOG, FACS: Thirteen percent, yes.

Shannon N. Westin, MD, MPH: Thirteen percent, and the tamoxifen not as much. I think it was a 0.0% response rate.

Michael J. Birrer, MD, PhD: I’d love to hear your opinion on it, Brad. Was that the response rate to pegylated liposomal doxorubicin? Two percent?

Bradley J. Monk, MD, FACS, FACOG: That’s right.

Michael J. Birrer, MD, PhD: What was it in your study?

Bradley J. Monk, MD, FACS, FACOG: Over 20%. How is that possible that a biased observer in an open-label trial, in a disease that’s hard to measure, could have a different result in a blinded independent central review? How is that possible? You can say, “I get it. Letrozole had some activity—half of what chemotherapy had in MILO. It had some. I think it’s a self-fulfilling prophecy. I don’t mean to say 1 trial was better than the other. I say it takes 2 trials to convince anyone of anything, and these trials are in contradiction.

Michael J. Birrer, MD, PhD: I could give you an alternative hypothesis. Maybe you had high-grades in your study.

Bradley J. Monk, MD, FACS, FACOG: In our study, to your point, we had independent pathology review by your pathologist.

Robert L. Coleman, MD, FACOG, FACS: Correct.

Michael J. Birrer, MD, PhD: There’s the problem.

Robert L. Coleman, MD, FACOG, FACS: You’re right, and we had central review for GOG-0281, as well.

Bradley J. Monk, MD, FACS, FACOG: That’s right. I think the take-home message is that clinical trial design matters, but I think that this is an active class of agents.

Shannon N. Westin, MD, MPH: Absolutely.

Bradley J. Monk, MD, FACS, FACOG: If you look at the progression-free survival of MILO and GOG-0281, the curves overlap.

Shannon N. Westin, MD, MPH: They’re right on top of each other, yes.

Bradley J. Monk, MD, FACS, FACOG: The only thing that’s different is the control arm.

Shannon N. Westin, MD, MPH: Yes.

Bradley J. Monk, MD, FACS, FACOG: And the way that the control arm was assessed. I’m not sure that 1 is positive or negative. I would hope that the NCCN [National Comprehensive Cancer Network] and others would recognize this class of agents as an opportunity.

Robert L. Coleman, MD, FACOG, FACS: I do too. This is a disease in which, because of a long postprogression survivorship, we end up going through all these agents.

Kathleen Moore, MD: Twice.

Bradley J. Monk, MD, FACS, FACOG: Twice, Katie Moore says.

Kathleen Moore, MD: Yes.

Robert L. Coleman, MD, FACOG, FACS: We need these options. The other thing that was interesting—that’s why I mentioned the crossover—was that when we looked at the efficacy in the crossover, we still saw…

Kathleen Moore, MD: It was less, though.

Robert L. Coleman, MD, FACOG, FACS: It was less, but it was 15%. The PFS was close to 10 months.

Shannon N. Westin, MD, MPH: Yes, 10 months.

Robert L. Coleman, MD, FACOG, FACS: We need this drug.

Bradley J. Monk, MD, FACS, FACOG: We do need this class of drug.

Robert L. Coleman, MD, FACOG, FACS: Class of drug. Yes, we need this class of drug.

Kathleen Moore, MD: You’re right. The studies were contradictory because of the control arm, but I also think they were consistent in that they showed efficacy. I agree with you. I feel like the NCCN should—I’m just going to say it—put it on compendium so we don’t have to fight for our patients.

Michael J. Birrer, MD, PhD: The other thing is that I think it’s already being used. We’ve been using it off-label for a long time.

Bradley J. Monk, MD, FACS, FACOG: It’s difficult to get reimbursed with that.

Robert L. Coleman, MD, FACOG, FACS: Getting back to the molecular biology in the tumor, both of these studies have pretty robust TR components coming. We’re going to dig into that.

Bradley J. Monk, MD, FACS, FACOG: In MILO, we reported that, and there was a KRAS-predictive biomarker.

Robert L. Coleman, MD, FACOG, FACS: The idea is that we’ve learned that it’s not necessarily just KRAS. It’s KRAS-specific mutation.

Bradley J. Monk, MD, FACS, FACOG: That’s true.

Robert L. Coleman, MD, FACOG, FACS: So we see different…with the KRAS G12D—the common ones—we don’t see as great of a discriminator, but we do see the G12Ds. I mean, Vs and Cs. In the Vs and Cs, we see a difference.

Michael J. Birrer, MD, PhD: In GOG-239 it was phospho-ERK. It was downstream. It was a very good marker.

Bradley J. Monk, MD, FACS, FACOG: We’re better at biomarkers now, I think.

Robert L. Coleman, MD, FACOG, FACS: It’s great.

Bradley J. Monk, MD, FACS, FACOG: It’s fun, huh? It’s fun. It’s fun to realize that ovarian cancer is heterogeneous. It’s fun to understand biomarkers, and it’s fun to give our patients—when I say fun, I mean satisfying. Fun is not the right word. It’s satisfying to help our patients with targeted therapy.

Transcript Edited for Clarity
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